Lipid particles of various sizes are employed for the controlled delivery of drugs. Hard gelatine capsules are filled with medicament-loaded lipid pellets with a size of approximately 0.10-2.0 mm, and the drug undergoes prolonged release from the lipid pellets, (commercial product Mucosolvan® [Müller, R. H., Feste Lipidnanopartikel [Solid lipid nanoparticles] (SLN), in Müller, R. H., Hildebrand, G. E. (eds.), Pharmazeutische Technologie: Moderne Arzneiformen [Pharmaceutical technology: modern dosage forms], Wissenschaftliche Verlagsgesellschaft Stuttgart, 357-366, 1998]). Lipid microparticles can be used for various application routes, from topical products (e.g. O/W creams) through oral medications to parenterals. An order of magnitude smaller are solid lipid nanoparticles (SLN®), which have an even wider range of use. Because of the fineness of the particle size, ophthalmological use is for example also possible.
Lipid particles can be employed in the form of a free-flowing dispersion, i.e. the lipid particles are dispersed in an aqueous phase (e.g. in isotonic glucose solution) or in a non-aqueous phase (e.g. in PEG 600 or oil). When used as a dispersion, the system must generally be free-flowing, i.e. of low viscosity. The lipid concentration in the dispersions is generally relatively low, in the range of approximately 1-100 (percent by weight). This is sufficient for most application purposes. If necessary, the lipid particle concentration may also be readily increased to up to 20% (similar to 20% oil containing emulsions for parenteral nutrition).
The situation regarding the required lipid concentration is different when incorporating lipid particles into traditional dosage forms such as creams, oral medicinal forms such as tablets, pellets or capsules, as well as in the case of parenterals with a limited injection volume. Substantially higher lipid concentrations are required here in order to reduce the proportion of water in the dispersion, which must be removed in order to produce the tablets, for example. This is true, in particular, when large amounts of lipid need to be incorporated into these medicinal forms, owing to the low medicament-loading capacity of the particles.
The incorporation of highly concentrated lipid particles into these medicinal forms is not difficult when relatively large particles are involved (>100 μm). The lipids can be ground to a coarse powder using a conventional mill. The particles thus obtained at a size of 100-200 μm are admixed as a powder in the production process of the dosage form.
The situation is more difficult with lipid microparticles and lipid nanoparticles. For lipid microparticles in the range of approximately 1-100 μm, highly energetic grinding is necessary in order to achieve this fineness of the particle size. The heat inevitably given off during the grinding process can partially melt the lipid and cause clumping; compensatory cooling is generally necessary. Fine powders, especially in the case of a hydrophobic surface, are susceptible to particle aggregation. In order to avoid this problem, wet grinding is essential, optionally with the addition of a surfactant. Highly fine lipid particles, i.e. in the range of a few micrometers and in particular in the nanometer range, cannot generally be produced by dry grinding. For wet grinding, the coarse lipid powder is dispersed in a liquid and is processed using an appropriate wet mill (e.g. colloid mill). Further possible modes of production include high pressure homogenisation methods [Müller, R. H., Feste Lipidnanopartikel (SLN), in Müller, R. H., Hildebrand, G. E. (eds.), Pharmazeutische Technologie: Moderne Arzneiformen, Wissenschaftliche Verlagsgesellschaft Stuttgart, 357-366, 1998] or alternatively precipitation [Morel, S., Ugazio, E., Cavalli, R., Gasco, M. R., Thymopentin in Solid Lipid Nanoparticles, Int. J. Pharm., 259-261, 1996]. Highly fine lipid particles can generally be incorporated into the aforementioned dosage forms only in the form of a dispersion.
Highly concentrated lipid particle dispersions are essential for the production of oral dosage forms and certain parenterals. For the production of tablets, for instance, the aqueous lipid particle dispersion is used as a granulating liquid. The volumes of aqueous lipid particle dispersion to be used for incorporating a particular amount of lipid particles as granulating liquid must not be too high, since otherwise too much water will need to be removed or granulation will no longer be even possible. Similar considerations apply to the use of aqueous lipid particle dispersions to make a paste of the excipient mixture for pellet extrusion. Soft gelatine capsules can be filled with non-aqueous lipid particle dispersions. When the lipid has a given maximum drug-loading capacity, the lipid particle dispersion must here also be sufficiently concentrated in terms of lipid particles in order not to exceed the maximum possible filling volume of the capsule.
This will be explained with reference to an example. The single dose of cyclosporin for adults is approximately 200 mg. The lipid nanoparticles produced by using cyclosporin have a maximum loading capacity of 20%, i.e. the lipid matrix consists of 200 mg of cyclosporin and 800 mg of lipid [Müller, R. H., Runge, S. A., Ravelli, V., Pharmazeutische Cyclosporin-formulierung mit verbesserten bio-pharmazeutischen Eigenschaften, erhöhter physikalischer Qualität and Stabillität sowie ein Verfahren zur Herstellung derselben [Pharmaceutical cyclosporin formulation with improved biopharmaceutical properties, higher physical quality and stability and a method for the production thereof], DE 198 19 273]. This single dose is to be administered in two tablets of 1 g each, i.e. 1 g of lipid/cyclosporin particles needs to be made into a paste with 1 g of excipients, for tabletting in the granulation process. At the current state of lipid nanoparticle production technology, 1 g of cyclosporin-loaded lipid nanoparticles is dispersed in 4 g of water (total volume of the aqueous lipid nanoparticle dispersion: approximately 5 ml=5 g). When mixing these 5 g with 1 g of tablet excipients, it is hence necessary to remove 4 g of water; 2 g of tablet mixture is obtained after the water is removed. It is clear that granulation is not possible with such low-concentration lipid nanoparticle dispersions (removal of 4 g of water from 6 g of granule mixture). Lipid particle dispersions with a lipid content of 50-70% are necessary. Similar problems are encountered in the case of a) drugs having on average a high single dose when incorporating drug-loaded lipid particles into any traditional dosage forms and b) drugs which, although they have a low single dose, are nevertheless difficult to incorporate into lipid particles (=low loading capacity).